Oxobenzofuran intermediates

ABSTRACT

A SERIES OF NOVEL 2-OXO-2,3-DIHYDROBENZOFURAN-3-CARBOXAMIDES HAVE BEEN PREPARED, INCLUDING THEIR PHARMACEUTICALLY ACCEPTABLE SALTS. THESE COMPOUNDS ARE USEFUL IN THERAPY AS NON-STERODIAL ANTI-INFLAMMATORY AGENTS. ALTERNATE METHODS OF PREPARATION ARE PROVIDED AND THE PRINCIPAL SYNTHETIC ROUTE IS DESCRIBED IN DETAIL.

United States Patent 3,829,446 OXOBENZOFURAN INTERMEDIATES Saul B.Kadin, New London, Conn., assignor to Pfizer Inc., New York, N.Y.

No Drawing. Original application Oct. 15, 1970, Ser. No. 81,162, nowPatent No. 3,676,463. Divided and this application Apr. 21, 1972, Ser.No. 246,491

Int. Cl. C07d /34 US. Cl. 260-3435 3 Claims ABSTRACT OF THE DISCLOSURE Aseries of novel 2-oxo-2,3-dihydrobenzofuran-3-carboxamides have beenprepared, including their pharmaceutically acceptable salts. Thesecompounds are useful in therapy as non-steroidal anti-inflammatoryagents. Alternate methods of preparation are provided and the principalsynthetic route is described in detail.

CROSS REFERENCE TO RELATED APPLICATION This application is a division ofapplication Ser. No. 81,162 filed Oct. 15, 1970 and now US. Patent3,676,- 463.

BACKGROUND OF THE INVENTION This invention relates to various new anduseful 2-oxobenzofuran carboxamides in the field of medicinal chemistry.More particularly, it is concerned with a series of 2oxo-2,3-dihydrobenzofuran-3-carboxamides, which are of especial value inview of their unique chemotherapeutic properties.

In the past, various attempts have been made by numerous investigatorsin the specialized field of synthetic organic medicinal chemistry toobtain new and useful antiinflammatory agents. For the most part, theseefforts have involved the synthesis and testing of various steroidalhormone compounds such as the corticosteroids. However, in the searchfor still newer and better or more improved anti-infiammtory agents, farless is known about the elfect of non-steroidal agents in this area,albeit this would be attractive since they would also necessarily lackthe untoward steroidal side-effects.

SUMMARY OF THE INVENTION In accordance with the present invention, ithas now been found that various novel 2-oxobenzofuran carboxamidecompounds, i.e., non-steroids, are surprisingly, extremely useful whenemployed in the field of drug therapy as anti-inflammatory agents. Morespecficially, the novel compounds of this invention are2-oxo-2,3-dihydrobenzofuran-3-earboxamides of the formula 5 3-CONHR andthe base salts thereof with pharmacologically acceptable cations,wherein X and Y are each a member selected from the group consisting ofhydrogen, fluorine, chlorine, bromine, alkyl and alkoxy each having fromone to five carbon atoms, trifiuoromethyl and trifiuoromethoxy; and R isa member selected from the group consisting of naphthyl, phenyl and monoand di-substituted phenyl wherein each substituent is chosen from thegroup consisting of fluorine, chlorine and bromine, alkyl having up tofour carbon atoms, alkoxy and thioalkoxy each having up to three carbonatoms, trifluoromethyl and trifluoromethoxy. These novel compounds areall useful in alleviating the painful effects caused 'by variousinflammatory conditions.

Of especial interest in this connection are such typical membercompounds of the invention as 2'-fiuoro-2-oxo- 2,3dihydrobenzofuran-3-carboxanilide, 4'-chloro-2-oxo- 2,3dihydrobenzofuran-3-carboxanilide, 2'-methyl-2-oxo 2,3-dihydrobenzofuran3 carboxanilide, 2'-methoxy-2-oxo-2,3-dihydr0benzofuran-3-carboxanilide,2-oxo-5-chloro-2,3-dihydrobenzofuran 3 carboxanilide, 4-chlor0-5-ch1oro-2-oxo-2,3-dihydrobenzofuran 3 carboxanilide, 2-oxo-5,6-dichloro-2,3-dihydrobenzofuran 3 carboxamilide,2'-lluoro-2-oxo-5,6-dichloro-2,3-dihydrobenzofuran- 3-carboxanilide and4'-ch1oro-2-oxo-5,6-dichloro-2,3-dihydrobenzofuran-3-carboxanilide. Itis to be understood that many of these compounds are potentiallytautomeric in nature and may exist in the enolic form with respect tothe 2-position of the molecule. All these compounds are extremely potentand possess anti-inflammatory activity to a significantly high degree.

Detailed Description of the Invention In accordance with the processemployed for preparing the novel compounds of this invention, anappropriately substituted 2,3-dihydrobenzofuran-2-one of the formula:

O/ZO Y is contacted with an organic isocyanate reagent of the formulaRNCO wherein R corresponds to the previously defined organic (aromatic)substituent on the nitrogen atom of the carboxamide moiety of thedesired final product. In this way, the corresponding 3-carboxamide(CONHR) compound is formed where X and Y are both defined as previouslyindicated. This particular reaction is normally conducted in a basicsolvent medium, most desirably employing a reaction-inert polar organicsolvent such as tetrahydrofuran, dimethylsulfoxide or dimethylformamideand preferably using a slight excess in moles of a base, liketriethylamine, on admixture with the solvent. Many of the aforesaidisocyanate reagents (RNCO) are either known compounds or else they caneasily be prepared from more readily available materials by usingmethods well-known to those skilled in the art. In practice, it isusually preferable to employ at least about a molar equivalent of theisocyanate reagent in the foresaid reaction of the present invention,with best results often being achieved by using a slight excess of same.Although any temperature below that of reflux may be used in order toeffect the reaction, it is normally found most convenient to employelevated temperatures in almost every case so as to shorten the requiredreaction time, which may range anywhere from several minutes up to about24 hours depending, of course, upo'n the-particular carboxamide compoundactually being prepared. Upon completion of the reaction, the product iseasily recovered from the spent reaction mixture by pouring same into anexcess of icewater containing a slight excess of acid, such ashydrochloric acid, whereby the desired carboxamide compound readilyprecipitates from solution and is subsequently collected by such meansas suction filtration and the like.

Another method for preparing the instant compounds of the inventioninvolves reacting a 2,3-dihydrobenzofuran-Z-one in the form of an alkalimetal or alkaline-earth metal salt with an appropriate1,1,3-trisubstituted urea of the formula (R) NCONHR, wherein R is anaryl group such as phenyl, p-chlorophenyl, p-bromophenyl, p-nitrophenyl,p-acetylaminophenyl, p-tolyl, p-anisyl, u-naphthyl, s-naphthyl, and thelike. This reaction is preferably carried out in the presence of areaction-inert polar organic solvent medium. Typical organic solventsfor use in this connectio include the N,N-dialkyl lower alkanoamideslike dimethylformamide, dimethylacetamide, diethylformamide anddiethylacetamide, as well as lower dialkyl sulfoxides such as dimethylsulfoxide, diethyl sulfoxide and di-n-propyl sulfoxide, etc. It isdesirable that the aforesaid solvent for this reaction be present insufiicient amount to dissolve each of the previously mentionedmaterials. In general, the reaction is conducted at a temperature thatis in the range of from about 20 C. up to about 150 C. for a period ofabout one-half to about ten hours. Recovery of the desired product fromthe reaction mixture is then most conveniently accomplished by firstdiluting the reaction solution with water and then adjusting the pH ofthe resulting aqueous solution to at least about pH 8.0, followed bysubsequent extraction of the basic aqueous solution with anywater-immiscible organic solvent in order to remove minor amounts ofunreacted or excess starting material that might possibly be present atthe stage. Isolation of the desired2-oxo-2,3-dihydrobenzofuran-3-carboxamide from the basic aqueous layeris then effected by the addition thereto of a dilute aqueous acidsolution, wherein the acid is present in such amount that it will causeprecipitation of the desired 2-oxobenzofuran carboxamide to occur fromthe aqueous solution.

In connection with a more detailed consideration of the aforesaidalternate method of synthesis for the compounds of this invention, therelative amounts of reagents employed are such that the molar ratio of2,3-dihydrobenzofuran-Z-one to the 1,1-diaryl-3-(monosubstituted)urea isdesirably in the preferred range of from about 1:1 to about 1:3,although substantially equimolar ratios will still cause equallysatisfactory results to be achieved. Nevertheless, an excess of thetrisubstituted urea is normally employed in this reaction since this notonly serves to cause a shift in the reaction equilibrium to the productside of the equation, but it is also additionally advantageous in thatthe excess reagent is easily removed after completion of the reaction bymeans of the solvent extraction step previously referred to. Moreover,it is to be noted that the formation of the carboxamide final productsof this invention is still further enhanced by the overall basiccharacter of=the general reaction mixture.

The two major type starting materials required for this reaction, viz.,the 2,3-dihydrobenzofuran-2-ones and the1,l-diaryl-3-(monosubstituted)ureas, are both readily available to thoseskilled in the art. For instance, the 2,3 dihydrobenZofuran-2-ones,which are also used as starting materials in the previously describedisocyanate method, are, for the most part, well-known in the chemicalprior art and/or can easily be synthesized in every case from morereadily available materials in accordance with standard organicprocedures that are commonly described therein [e.g., see Elderfield etal., in Heterocyclic Compounds, Vol. 2, John Wiley & Sons, Inc., NewYork, N.Y. (1951), pp. 3-4, for a brief description of the generalreaction involving lactone formation with the correspondingo-hydroxyphenylacetic acid compounds]. The1,1-diaryl-3-(rnonosubstituted)ureas, on the other hand, are all readilyprepared from common organic reagents by employing standard proceduresWell known in the art, e.g., the desired 1,1,3-trisubstituted urea maybe prepared from the corresponding disubstituted carbamyl chloride andthe appropriate amine (RNH in accordance with the general procedure ofReudel, as described in Recueil des T ravaux Chimiques des Pays-Bats",Vol. 33, p. 64 (1914).

The chemical bases which are used as reagents in this invention toprepare the pharmaceutically acceptable salts of same are those whichform non-toxic salts with the many herein described acidic2-oxo-2,3-dihydrobenzofuran-3-carboximides, such as2-fiuoro-2-oxo-2,3-dihydrobenzofuran-3-carboxanilide, for example. Theseparticular non-toxic base salts are of such a nature that their cationsare essentially nontoxic in character over the wide range of dosageadministered. Examples of such cations include those of sodium,potassium, calcium and magnesium, etc. These salts can easily beprepared by simply treating the aforementioned 2oxo-2,3-dihydrobenzofuran-3-carboxamides with an aqueous solution of thedesired pharmacologically acceptable base, i.e., those oxides,hydroxides or carbonates which contain pharmacologically acceptablecations, and then evaporating the resulting solution to dryness whileunder reduced pressure. Alternatively, they may also be prepared bymixing lower alkanolic solutions of the said acidic compounds and thedesired alkali metal alkoxide together, and then evaporating saidresulting solution in the same manner as before. In either case,stoichiometric amounts of reagents must be employed in order to ensurecompleteness of reaction, with consequent maximum production of yieldsof the desired pure product.

As previously indicated, the 2-oxo-2,3-dihydrobenzofuran-3-carboxamidecompounds of the present invention are all readily adapted totherapeutic use as anti-inflammatory agents, particularly in view oftheir ability to reduce the swelling and relieve the pain caused byarthritic and othher inflammatory disorders that are normally associatedwith such basic ailments as rheumatoid arthritis and the like. Forinstance, 2-oxo-5-chloro-2,3-dihydrobenzofuran-3-carboxanilide, atypical and preferred agent of the present invention, exhibitsremarkable activity in the standard carrageenin-induced rat foot edematest [described by C. A. Winter et al., Proc. Soc. Exp. Biol., Vol. 111,p. 544 (1962)], where it was found to cause a strikingly significantinhibition in swelling at the 1.0 mg./ kg. dose level. Morespecifically, 2-oxo-5-chloro-2,3-dihydrobenzofuran-3-carboxanilide hasbeen found to exhibit its aforesaid non-steroidal therapeutic effect inrats when tested orally at levels ranging from 0.33-33 mg./kg., Withsaid compound even retaining its extremely potent antiinfiammatoryactivity in adrenalectomized animals to a significantly high degree.Additionally, none of these compounds cause any substantial side elfectsto occur in the subjects to whom they are so administered, i.e., noproblems of toxicity or of a harmful pharmacological nature, eithergross or microscopic, are encountered when said compounds areadministered for the aforestated purposes.

in the manner described as indicated above.

In accodance with a method of treatment of the present invention, theherein described 2-oxo-2,3-dihydrobenzofuran-3-carboxamideanti-inflammatory agents can be administered to an afilicated subjectvia either the oral or parenteral routes of administration. In general,these compounds are most desirably administered in doses ranging fromabout mg. up to about 1000 mg. per day, although variations will stillnecessarily occur depending upon the weight of the subject beingtreated. However, a dosage level that is in the range of from about 1.6mg. to about 16 mg. per kg. of body weight per day is most desirablyemployed in order to achieve effective results. Nevertheless, it isstill to be appreciated that other variations may also occur in thisrespect, depending upon the species of animal being treated and itsindividual response to said medicament, as well as on the particulartype of pharmaceutical formulation chosen and the time period andinterval at which such administration is carried out. In some instances,dosage levels below the lower limit of the aforesaid range may be morethan adequate, while in other cases still larger doses may be employedwithout causing any harmful or deleterious side effects to occurprovided that such higher dose levels are first divided into severalsmaller doses that are to be administered throughout the day.

In connection with the use of the2-oxo-2,3-dihydrobenzofuran-3-carboxamide compounds of this inventionfor the treatment of arthritic subjects, it is to be noted that they maybe administered either alone or in combination with pharmaceuticallyacceptable carriers by either of the routes previously indicated, andthat such administration can be carried out in both single and multipledosages. More particularly, the novel compounds of the invention can beadministered in a wide variety of different dosage forms, i.e., they maybe combined with various pharmaceutically-acceptable inert carriers inthe form of tablets, capsules, lozenges, troches, hard candies, powders,sprays, creams, salves, suppositories, jellies, pastes, lotions,ointments, aqueous suspensions, injectable solutions, elixirs, syrupsand the like. Such carriers include solid diluents or fillers, sterileaqueous media and various non-toxic organic solvents, etc. Moreover,such oral pharmaceutical compositions can be suitably sweetened and/orflavored by means of various agents of the type commonly employed forjust such a purpose. In general, the therapeutically-effective compoundsof this invention are present in such dosage forms at concentrationlevels ranging from about 0.5% to about 90% by weight of the totalcompositions, i.e., in amounts which are sufficient to provide thedesired unit dosage.

For purposes of oral administration, tablets containing variousexcipients such as sodium citrate, calcium carbonate and dicalciumphosphate may be employed along with various disintegrants such asstarch and preferably potato or tapioca starch, alginic acid and certaincomplex silicates, together with binding agents such aspolyvinylpyrrolidone, sucrose, gelatin and acacia. Additionally,lubricating agents such as magnesium stearate, sodium lauryl sulfate andtalc are often very useful for tabletting purposes. Solid compositionsof a similar type may also be employed as fillers in soft andhard-filled gelatin capsules; preferred materials in the connectionwould also include lactose or milk sugar as well as high molecularweight polyethylene glycols. When aqueous suspension and/ or elixirs aredesired for oral administration, the essential active ingredient thereinmay be combined with various sweetening or flavoring agents, coloringmatter or dyes, and, if so desired, emulsifying and/ or suspendingagents as well, together with such diluents as water, ethanol, propyleneglycol, glycerin and various like combinations thereof.

For purposes of parenteral administration, solutions of these particular2-oxo-2,3-dihydrobenzofuran-3-carboxamides in either sesame or peanutoil or in aqueous propylene glycol may be employed, as well as sterileaqueous solutions of the corresponding water-soluble alkali metal oralkaline-earth metal salts previously enumerated. Such aqueous solutionsshould be suitably buffered if necessary and the liquid diluent firstrendered isotonic with suflicient saline or glucose. These particularsolutions are especially suitable for intravenous, intramuscular andsubcutaneous injection purposes. Additionally, it is also possible toadminister the aforesaid 2-oxobenzofuran carboxamide compounds topicallywhen treating inflammatory conditions of the skin and this may bepreferably done by way of creams, salves, jellies, pastes, ointments andthe like, in accordance with standard pharmaceutical practice.

A general procedure employed for detecting and comparing theanti-inflammatory activity of the compoupnds of the present inventionis, as previously indicated, the standard carrageenin-induced rat footedema test using the aforementioned technique of C. A. Winter et al. Inthis test, anti-inflammatory activity is determined as the inhibition ofedema formation in the hind paw of male albino rats (weighing 150-190g.) in response to a subplantar injection of carrageenin. Thecarrageenin is injected as a 1% aqueous suspension (0.05 ml.) one hourafter oral administration of the drug, which is normally given in theform of an aqueous solution. Edema formation is then assessed threehours after the carrageenin injection by measuring the volume of theinjected paw initially as well as at the three-hour mark. The increasein volume three hours after carrageenin injection constitutes theindividual response. Compounds are considered active if the responsebetween the drug-treated animals (six rats/group) and the control group(i.e., animals receiving the vehicle alone) is deemed to be significanton comparison with results afforded by standard compounds likeacetylsalicylic acid at mg./kg. or phenylbutazone at 33 mg./kg., both bythe oral route of administration.

Example I 2-Methoxy-S-chlorophenoxyacetic acid was obtained by treating2-methoxy-5-chlorobenzaldehyde according to the method of Levin et al.[Journal of the American Chemical Society, Vol. 70, p. 1930 (1948)] togive a pure product melting at 127-129 C. A mixture consisting of 28.5g. (0.135 mole) of glacial acetic acid, 86 ml. of 48% hydrobromic acidand 8.6 ml. of hydriodic acid was then refluxed for a period of 18hours. After cooling to room temperature, the reaction mixture wasdiluted with 200 ml. of ice water and treated with a few sodiumbisulfite crystals to remove the dark color. It was then extracted with40 ml. of chloroform, followed by three- 100 ml. portions of diethylether. The combined ether layers were saved, dried over anhydrousmagnesium sulfate and subsequently evaporated to dryness while underreduced pressure. In this manner, a 24 g. (95%) yield of2-hydroxy-S-chlorophenylacetic acid was obtained as residue in the formof a yellow crystalline solid, m.p. 128- 130 C.

Analysis:

Calcd. for c H ClO C, 51.49; H, 3.78. Found: C, 51.24; H, 3.79.

This material was then cyclized by refluxing 600 mg (3.22 mole) of samein a benzene (10 ml.) solution containing a catalytic amount ofp-toluenesulfonic acid, with the water being removed by means ofazeotropic distillation. Upon completion of this step (as revealed bythin layer chromatography), water was added to extract the catalyst,followed by washing with 5 ml. of 1N sodium carbonate solution to removeany unreacted starting material. After further washing the reactionmixture with saturated aqueous sodium chloride solution, the benzenelayer was dried over anhydrous magnesium sulfate and subsequentlyevaporated to dryness while under reduced pressure to afford 510 mg. (95of 5-chloro-2,3-dihydrobenzofuran-Z-one, m.p. 127129 C.

Analysis:

Calcd. for C H ClO: C, 57.00; H, 2.99. Found: C, 57.09; H, 2.99.

Example II A stoichiometrical amount (8.0 g., 0.113 mole) of chlorinegas dissolved in 100 ml. of carbon tetrachloride was added to 17.7 g.(0.113 mole) of freshly distilled 2- methoxy-4-chloro-toluene (i.e.,5-chloro-2-methylanisole, b.p. 106-111 C./35 mm. Hg) at ice-coldtemperatures (05 C.), and the resulting mixture was then allowed to stirat room temperature (-25 C.) for a period of 18 hours. Fractionaldistillation of the spent mixture then gave 10.7 g. (50%) of4,5-dichloro-2-methylanisole, lip. 144145 C./35 mm. Hg.

Analysis Calcd. for C H CI O: C, 50.29; H, 4.22. Found: C, 49.71; H,4.24.

A solution consisting of 24.68 g. (0.129 mole) of 4,5-dichloro-Z-methylanisole dissolved in ml. of chloroform was then treatedat reflux temperature with 20.6 g. (0.129 mole) of bromine (6.9 ml.)dissolved in 50 ml. of chloroform. The bromine solution was added in adropwise manner during the course of a 1.5-hour period and uponcompletion of same, refluxing was continued for an additional hour. Thereaction mixture was then subjected to further treatment with bromine(6.86 g., 0.043 mole), using the same procedure as before and finallyallowed to stand overnight at room temperature (-25 C.) for a period of16-18 hours. Upon evaporation of the solvent, followed by fractionaldistillation of the resulting oily residue, there were obtained 28.7 g.(83%) of 4,5-dichloro-2-lbromoethylanisole, b.p. 130-135 C./0.2 mmg. Hg.

A solution consisting of 25.93 g. (0.0975 mole) of the above4,5-dichloro-Z-bromomethylanisole dissolved in 50 m1. of ethanol wasslowly added (i.e., dropwise) to a solution of 5.9 g. (0.120 mole) ofsodium cyanide dissolved in 6 ml. of warm water. The total time requiredfor the addition amounted to 45 minutes. The reaction mixture was thenrefluxed for a period of 2.5 hours, followed by removal of the solventunder reduced pressure. The residue was subsequently dissolved in'methylene chloride and washed with two-100 ml. portions of cold water.After drying over anhydrous magnesium sulfate and evaporating the driedsolvent filtrate under reduced pressure, there were obtained 20.5 g.(97%) of 4,5-dichloro- -Z-methoxyphenylacetonitrile as a solid product,m.p. 74- 77 C. Recrystallization from ethanol then raised the meltingpoint to 8285 C.

Analysis Calcd. for C H- Cl NO: C, 50.23; H, 3.25; N, 6.46. Found: C,49.86; H, 3.21; N, 6.62.

A mixture of 20.5 g. (0.093 mole) of 4,5-dichloro-2-methoxyphenylacetonitrile in 150 ml. of ethanol and 100 ml. of 3Naqueous potassium hydroxide (0.250 mole) was refluxed for a period ofapproximately 16 hours. Upon completion of this step, the ethanol wasremoved by means of evaporation and the basic aqueous residue thereafterwashed with three-100 ml. portions of chloroform, followed byacidification at C. with 3N hydrochloric acid. The white precipitatewhich formed at this point was recovered by suction filtration andrecrystallized from methanol to give 14.52 g. of pure 4,5-dichloro-2-methoxyphenylacetic acid, m.p. 170-172 C. A second crop of crystals(m.p. 168-171 C.) weighing 1.93 g. was then obtained from the motherliquor. The total yield of material amounted to 75% of the theoreticalvalue.

Analysis.

Calcd. for C H Cl O C, 46.19; H, 3.42; CI, 30.05. Found: C, 46.26; H,3.73; Cl, 29.79.

2-Methoxy-4,5-dichlorophenylacetic acid (16.4 g., 0.070 mole), preparedas described above, was then refluxed with 45 ml. of glacial aceticacid, 45 ml. of 48% hydro bromic acid and 4.5 ml. of hydriodic acid fora period of hours. On cooling to room temperature and diluting themixture with 150 ml. of ice water, there was obtained a dark-redsolution that was subsequently treated with a few sodium bisulfitecrystals, followed by extraction with 10 m1. of chloroform and three-50ml. portions of diethyl ether. The combined ether layers were saved,dried over anhydrous sodium sulfate and thereafter evaporated to drynesswhile under reduced pressure to give a white solid material as residue.

The material obtained above, which was essentially pure2-hydroxy-4,5-dichlorophenylacetic acid (11.5 g., 0.049 mole), was thenrefluxed in benzene (100 ml.) with a catalytic amount ofp-toluenesulfonic acid for a period of 2.5 hours, with water beingremoved by means of azeotropic distillation. Upon completion of thisstep, the mixture was cooled and subsequently treated with 10 m1. of 1Naqueous potassium hydroxide solution, followed by drying over anhydrousmagnesium sulfate. After removal of the drying agent by means offiltration and the solvent by means of evaporation under reducedpressure, there were obtained 9.3 g. of crude product which, afterrecrystallization from isopropanol, gave 7.85 g. of pure5,6-dichloro-2,3-dihydrobenzofuran-2-one, m.p. 94-96 C. A secondcrystalline crop (1.9 g.) was then obtained from the mother liquor. Thetotal yield of final product amounted to 97% of the theoretical.

Analysis Calcd. for C H Cl O C, 47.33; H, 1.98.

Found: C, 47.24; H, 2.10.

Example III Employing the procedures described in the previous twoexamples, the following 2,3-dihydrobenzofuran-2- ones are prepared bycondensing the corresponding r ngsubstituted 2-hydroxyphenylacetic acidsin the appropriate manner:

X Y H 7-Cl 4-CH H H 7(n-C H 5-OC5H11(I1) 6'Oc5H11(n) 4-(I1-C5H11) H 4-Cl7-Cl H 6-CF 5-F 6-F 4-Cl H 4-Br H 5-CF 6-CF 4CF H H 6-OC5H11(II) 5 i1)6-(l'l-C H CF '6-OCF 4-OCH H H 6-F 5-Br H 2 5 6-OC H 5-Cl 4-C H H 2 56-C H 4-OCF H H 6-OCH 5-Br 4-F H 4"(I1-C4H9) H S'OCgH H 7-OCF S-F H 3-0014 5-Cl 7 1 Example IV A slurry of 0.44 g. (0.011 mole) of sodiumhydride (60.2% dispersion in mineral oil) suspended in 5.0 ml. of drydimethylformamide was slowly stirred at ice-cold temperatures (0l0 C.),while a solution consisting of 1.34 g. (0.010 mole) of2,3-dihydrobenzofuran-2-one dissolved in 3.0 ml. of drydimethylformamide was subsequently added thereto, in a dropwise manner,with continued stirring and cooling being maintained throughout thecourse of the additlon step. At this point, 1.19 g. (0.01 mole) ofphenyl isocyanate were next added dropwise to the mixture, followed byfoaming and gas evolution until the reaction was essentially complete(as revealed by thin layer chromatography). Upon termination of thisstep, the resulting mixture was cooled in an ice-Water bath and thenslowly poured into a mixture of ice water containing 14 ml. of 1Nhydrochloric acid. The precipitate which formed at this point wasrecovered by means of suction filtration and vacuum dried in an oven toafford 2.59 g. of material melting at l45-155 C. Recrystallization ofthe latter material 9 from ethanol then gave 0.78 g. (31%) of2-oxo-2,3-dihydrobenzofuran-3-carboxanilide, m.p. 179-181 C.

Analysis Calcd. for C H NO C, 71.14; H, 4.38; N, 5.53. Pounds: C, 71.27;H, 4.45; N, 5.60.

Example V The procedure described in Example IV Was repeated using 1.35g. (0.010 mole) of o-tolyl isocyanate in place of 1.19 g. (0.010 mole)of phenyl isocyanate. In this particular case, the corresponding finalproduct thus obtained was 2'-methyl-2-oxo-2,3-dihydrobenzofuran 3carboxanilidc (0.85 g.), m.p. 164-165 C. after recrystallization frombenzene.

Analysis Calcd. for C H NO C, 71.90; H, 4.90; N, 5.24. Found: C, 72.07;H, 4.91; N, 5.24.

Example VI The procedure described in Example IV was repeated using 1.49g. (0.010 mole) of a-methoxyphenyl isocyanate (i.e., o-anisylisocyanate) in place of 1.19 g. (0.010 mole) of phenyl isocyanate. Inthis particular case, the corresponding final product thus obtained was2'-methoxy-2- oxo-2,3-dihydrobenzofuran-3-carboxanilide (1.05 g.), m.p.142-143 C. after recrystallization from ethyl acetate.

Analysis.

Calcd. for C H NO C, 67.84; H, 4.62; N, 4.95. Found: C, 68.05; H, 4.61;N, 4.95.

Example VII To a well-stirred mixture immersed in an ice bath consistingof 2.68 g. (0.020 mole) of 2,3-dihydrobenzofuran- 2-one and 2.22 g.(0.022 mole) of triethylamine in 5.0 ml. of dimethylformamide, therewere simply added in a dropwise manner, 3.02 g. (0.022 mole) ofo-fluorophenyl isocyanate, with constant agitation being maintainedthroughout the course of the entire addition step. The resultingreaction mixture was then stirred at room temperature -25 C.) forapproximately one hour (30-90 minutes), and thereafter poured into coldwater and partitioned between 200 ml. of ethyl acetate and 25 ml. of 1Naqueous sodium hydroxide solution. The basic aqueous layer whichseparated at this point was then saved and next added to an ice-watermixture containing 15 ml. of 6N hydrochloric acid to give a heavycrystalline precipitate. The latter material was subsequently collectedby means of suction filtration and air-dried to constant weight toafford a 2.2 g. (46%) yield of 2'fluoro-2-oxo-2,3-dihydrobenzofuran-3-carboxanilide, m.p. 157-158 C. after one recrystallization frombenzene-hexane (4:1 by volume).

Analysis Calcd. for C H FNO C, 66.42; N, 3.72; N, 5.17. Found: C, 66.28;H, 3.70; N, 5.07.

Example VIII The procedure described in Example VII was repeated using3.38 g. (0.020 mole) of -chloro-2,3-dihydrobenzofuran-Z-one, 2.62 g.(0.022 mole) of phenyl isocyanate and 2.22 (0.022 mole) of triethylaminein ml. of dry dimethylformamide. In this particular case, thecorresponding final product thus obtained was 2-oxo-5-chloro-2,3-dihydrobenzofuran-3-carboxanilide, m.p. 186-188 C. afterrecrystallization from benzene.

Analysis Calcd. for C H CINO C, 62.63; H, 3.50; N, 4.87. Found: C,62.51; H, 3.52; N, 4.69.

Example IX The procedure described in Example VII was repeated toprepare the following 2-ox0-2,3-dihydrobenzofuran-3- carboxanilides,starting from 2,3-dihydrobenzofuran-2-one 10 and the appropriate phenyl,tolyl or anisyl isocyanate in each case:

M.p., C.

3-methy1-2-oxo-2,3-dihydrobenzofuran-3- carboxanilide 158-1594'-methyl-2-oxo-2,3-dihydrobenzofuran-3- carboxanilide 173-1744'-fluoro-2-oxo-2,3-dihydrobenzofuran-3- carboxanilide 175-1772'-chloro-2-oxo-2,3-dihydrobenzofuran-3- carboxanilide -1423-chloro-2-oxo-2,3-dihydrobenzofuran-3- carboxanilide 183-1844-chloro-2-oxo-2,3-dihydrobenzofuran-3- carboxanilide 184-1854'bromo-2-oxo-2,3-dihydrobenzofuran-3- carboxanilide 199-2004-methoxy-2-oxo-2,3-dihydrobenzofuran-3- carboxanilide 204-2054-ethoxy-2-oxo-2,3-dihydrobenzofuran-3- carboxanilide 183-185 EXAMPLE XTo a well-stirred, ice-cold mixture of 655 mg. (0.0055 mole) of phenylisocyanate and 0.78 ml. of triethylamine (0.0055 mole) in 5.0 ml. ofdirnethylformamide, there was added in a dropwise manner 1.0 g. (0.0050mole) of 5,6 dichloro 2,3 dihydrobenzofuran 2 one that had previouslybeen dissolved in 5.0 ml. of dry dimethylformamide. Constant agitationwas maintained throughout the course of the addition, which was completein about five minutes, followed by further stirring of the reactionmixture at 0 C. for an additional period of five minutes. Uponcompletion of this step, the resulting mixture was poured into 20 ml. ofice water and thereafter treated with 10 m1. of 1N aqueous potassiumhydroxide and 5 ml. of dry ethyl acetate. The basic aqueous layer whichseparated at this point was then saved and added to an icewater mixturecontaining 5 ml. of concentrated hydrochloric acid, whereupon acream-colored crystalline precipitate soon formed. The latter materialwas subsequently collected on a filter funnel and air-dried to constantweight to give 0.568 g. (38%) of 2 oxo 5,6 dichloro 2,3-

dihydrobenzofuran-3-carboxanilide, m.p. 210-212 C.

Analysis.-Calcd. for C H Cl NO C, 55.92; H, 2.82; N,

4.35. Found: C, 55.92; H, 2.90; N, 4.44.

Example XI The procedure described in Example X was repeated using 3.38g. (0.0022 mole) of p-chlorophenyl isocyanate and 2.22 g. (0.0022 mole)of triethylamine in 10 ml. of dimethylforrnamide, together with 3.38 g.(0.0020 mole) of 5 chloro 2,3 dihydrobenzofuran 2 one also dissolved in10 ml. of dimethylformamide. In this particular case, the correspondingfinal product thus obtained was 4 chloro 2 oxo 5 chloro 2,3dihydrobenzofuran 3 carboxanilide, m.p. 222-223" C. afterrecrystallization from isopropanol.

Analysis.-Calcd. for C H Cl NO C, 55.92; H, 2.82; N,

4.35. Found: C, 56.15; H, 3.10; N, 4.32. 1

Example XII The procedure descibed in Example X was repeated to preparethe following 2 oxo 2,3 dihydrobenzofuran- 3 carboxanilides, startingfrom either 5 chloro 2,3- dihydrobenzofuran 2 one or 5,6 dichloro 2 oxo-2,3 dihydrobenzofuran 2 one, as the case may be, and the appropriatephenyl, tosyl or anisyl isocyanate reagent in each instance:

M.p. C. 2-methyl-2-oxo-5-chloro-2,3-dihydrobenzofuran- 3-carboxanilide196-198 3'-methy1-2-oxo-5-chloro-2,3-dihydrobenzofuran- 3-carboxanilide181-183 M.-p. C. 4'-methyl-2-oxo-5-chloro-2,3-dihydrobenzofuran-3-carboxanilide 201-203 2-chloro-2-oxo-5-chloro-2,3-dihydrobenzofuran--3-carboxanilide 147-148 3'-chloro-2-oxo-5-chl0ro-2,3-dihydrobenzofuranlt-carboxanilide 176-177 2'-methoxy-2-oxo-5-chloro-2,3-dihydrobenzofuran-3-carboxanilide 131-132 4-methoxy-2-oxo-5-chloro-2,3-dihydrobenzofuran-3-carboxanilide 208-2093'-chloro-2-oxo-5,6-dichloro-2,3-dihydrobenzofuran- 3-carboxanilide207-209 4'-chloro-2-oxo-5,6-dichloro-'2,3-dihydrobenzofuran-3-carboxanilide 216-2182'-methoxy-2-oxo-5,6-chloro-2,3-dihydrobenzofuran- 3-carboxanilide150-152 Example XIII The procedure described in the preceding examplesis employed once again to prepare the following 2-oxo-2,3-dihydrobenzofuran 3 carboxamides, starting from the corresponding 2,3dihydrobenzofuran 2 one and the appropriate organic isocyanate reagentin each case:

W o ONHR LV X Y R H H 2,4-difiuoroph enyl -0 C2H5 6-0 02H;3-br01nophenyl 5-Cl H 2-0Fa-pheny1 5-01 6-F 2,5-dimethoxyphenyl. H HZ-ethylphenyl; 4-02H H henyl. 5-01 6-01 a-naphthyl. 5-C2Hs G-CzHsB-naphthyl. 4-0 0 Fa H 4-0 Fzo-phenyl 6-0 0H 2-chloropheny1. 5-Br fi-Br8-ehlorophenyl. 4-F H d-chloroph enyl 4-(I1-C4H9) H 2-meth ylpheuyl. 5-002H H 3-methy1pheny1. H 7-0 0F; 4-methylpheny1. 4-01 H 2-methoxypheny1 HH 2-thioethoxypheny1. 5-F H 4-rnethoxypheny1. 5-0H; 6-0Ha2,5-dich1orophenyl. 5-0 0H; 6-0 0H; 3,4-dimethy1phenyl: H H2,5-dichrophenyl. H 7-01 4-(n-buty1) phenyl. H H 3-0Fa-ph enyl. 5-131' H3,5difluorophenyl 4-0Ha H 2,4-d1methoxyphenyl H 7- (n-04Hv)2,5-dimethoxyphenyl H H 2-ethoxyphenyl. 5-0 C Hu(n) 6-0 0 Hn(n)4-ethoxyphenyl H H 3-isopropoxypbenyl; 5-F H tenyl. 4-(n-G Hn) Ha-naphthyl. 4-01 7-01 B-naphthyl H 6-0 F; 2-th1ometh oxyph enyl 5-F 6-F4-bromophenyl' H H 3-fiuorophenyl. 5-C1 H S-CFa-phenyl. 5-0 F: 6-0 F;2,3-dichlorophenyl 5-01 H 5-01-2-methoxypheny1; 5-01 6-013,5-dich1oropheny1 4-0Fa H 3,5-dimethoxyphenyl. H H 4-thlopropoxyphenyl.

7-0 C5H11(n) 2,6-dlmethylpheny1. 5 (n-0 Hu) 6- (n-0 Hn)Z-CHzO-S-methylphenyl.

H 3-01-4-methy1phenyl. 5-0 CFa 6-0 CF: 2,4-dimethylphenyl 4-0 CHa H2-O1-5-CFa-phenyl. H fi-F 3-0Fa0-phenyl. 5-Br H 2,4-difluoropheny1. 5-017-01 Phenyl. H H 4-(n-butyl) phenyl. H H 3-methoxypheny1. H H2-CF;O-pheny1. 4-Br H 2,5-d1fluoro'ph enyl 4-01 7-01 Phenyl H H4-isopr0py1. H H 4-0 Fg-phenyl.

12 Example XIV The sodium salt of 2' iluoro 2 oxo 2,3 dihydrobenzofuran3 carboxanilide is prepared by dissolving said compound in anhydrousmethanol and then adding said solution to another methanolic solutionwhich contains an equivalent amount in moles of sodium methoxide. Uponsubsequent evaporation of the solvent therefrom via freezing-drying,there is obtained the desired alkali metal salt in the form of anamorphous solid powder which is freely soluble in water.

In like manner, the potassium and lithium salts are also prepared as arethe alkali metal salts of all the other acidic 2 oxo 2,3dihydrobenzofuran 3 carboxamides of this invention, which were reportedpreviously in the preceding examples.

Example XV Example XVI A dry solid pharmaceutical composition isprepared by blending the following materials together in the proportionsby weight specified below:

2-Oxo-5-chloro-2,3-dihydrobenzofuran-3- carboxanilide 50 Sodium citrate25 Alginic Acid 10 Polyvinylpyrrolidone 10 Magnesium stearate 5 Afterthe dried composition is thoroughly blended, tablets are punched fromthe resulting mixture, each tablet being of such size that it containsmg. of the active ingredient. Other tablets are also prepared in asimilar fashion containing 5, 10, 25 and 50 mg. of the activeingredient,

respectively, by merely using the appropriate amount of theoxobenzofuran carboxamide compound in each case.

Example XVII A dry solid pharmaceutical composition is prepared bycombining the following materials together in the proportions by weightindicated below:

2'-Methyl-2-oxo-2,3-dihydrobenzofuran-3- carboxanilide 50 Calciumcarbonate 20 Polyethylene glycol, average molecular weight 4000 30 Thedried solid mixture so prepared is then thoroughly agitated so as toobtain a powdered product that is completely uniform in every respect.Soft elastic and hard-filled gelatin capsules containing thispharmaceutical composition are then prepared, employing a sufficientquantity of material in each case so as to provide each capsule with 250mg. of the active ingredient.

Example XVIII The following 2 oxo 2,3 dihydrobenzofuran 3-carboxanilides were tested for anti-inflammatory activity in rats, usingthe carrageenin-induced rat foot edema test, and were found to be activeorally at the dosage levels indicated below (these actually representthe minimum eifective dose):

X C ONHR Y 0 L0 D osage X Y R (mg. lkg.)

H H Phenyl. 33 H H 2-methylphenyl 3. 3 H H 3-methylphenyL. 33 H H4-methylphenyl 33 H H 2-fluorophenyl. 3. 3 H H 4-fluoropheny1: 33 H H2-ehlorophenyl; 33 H H 3-ehloropheny1 33 H H 4-oh1orophenyl. 10 H H4-bromophenyl" 100 H H Z-methoxypheiiyl. 10 H H 4-methoxyphenyl. 33 H Hkethoxyphenyl- 33 01 H Phenyl 1.0 01 H 2-methylph enyl 33 01 H3-methylphenyl 100 01 H 4-methylpheny1 100 01 H 2ehloropheny1. 33 C1 H 3eh1orophenyL 33 01 H 4-ehloroph enyl 10 01 H 2-methoxypheny1- 100 01 H-methoxyphenyl 100 C1 C1 Phenyl 10 C1 C1 B-chlorophenyl- 38 C1 C14-eh1oropheny1 10 C1 C1 2-metlzoxyphenyl 33 C1 C1 4-methoxyphei1yl- 100C1 C1 2-flnorophenyl 10 14 What is claimed is: 1. A benzofuran-2-one ofthe formula:

References Cited FOREIGN PATENTS 6/1970 Germany 260343.4 4/1972 Belgium260-343,.3

DONALD G. DAUS, Primary Examiner A. M. T. TIGHE, Assistant Examiner

